The chemistry of cyclic polyamines, and in particular of tetraazacycloalkanes, the two main representatives of which are 1,4,7,10-tetraazacyclododecane (cyclen) and 1,4,8,11-tetraazacyclotetradecane (cyclam), has expanded considerably. The derivatives of these polyazamacrocycles find applications in fields as diverse as the purification of liquids, catalysis or medicine. Cyclen is, for example, the base unit of numerous contrast agents in medical imaging. The N-functionalization of these macrocycles and the study of the complexing properties of the novel ligands thus obtained have formed the subject of numerous studies.
The selectivity of the macrocycle with respect to a given substrate depends on the nature, on the number and on the relative position of the chelating arms. Most applications require the fixing of the macrocycles, either to a solid support or to an antibody. The synthesis of molecules comprising both a complexing site, such as a nitrogenous macrocycle carrying suitable chelating arms, and a reactive ending which makes possible grafting to an antibody or to a solid support has formed the subject of numerous publications and patent applications over the last decade. However, such bifunctional chelating agents (BCA or BFC) are difficult to prepare, in particular when different functional groups have to be condensed to the nitrogen atoms of the ring.
Numerous relatively selective methods for the N-functionalization of tetraazacycloalkanes have been described. In point of fact, most of them require either the use of a large excess of the base macrocycle, still relatively expensive, or the tedious implementation of successive sequences of protection and of deprotection of reaction sites.
Another approach consists in introducing the arm which makes possible the grafting onto a carbon atom of the macrocycle backbone and then the chelating arms onto the nitrogen atoms. The latter approach appears better suited to the synthesis of these bifunctional chelating agents as it makes it possible, on the one hand, to retain the four secondary amine functional groups without detrimentally affecting the properties of the macrocycle and, on the other hand, to easily attach four chelating arms during a stage of complete N-functionalization. This approach has been applied in the synthesis of numerous bifunctional chelating agents, some of which, represented in FIG. 1, are used in clinical trials on human beings and/or are available commercially (BAT, p-NCS-Bz-DOTA, p-NH2-Bz-DOTA). However, it remains limited by the problematic synthesis of the C-functionalized macrocycles.
This is because a synthesis by formation of a C-C bond to the macrocycle cannot be envisaged. It necessarily involves the use of a synthon carrying the desired functional group or an intermediate which makes possible access to the latter. Several cyclization methods have been developed. None is general and allows access without distinction to the cyclam, to the cyclen or to other macrocycles.
In the case of cyclam derivatives, the most widely used method to date is that of Tabushi et al., represented by scheme 1, based on the condensation of a linear tetraamine with a functionalized diethyl malonate1. This is because the acidity of the hydrogen atoms of the methylene group makes possible easy functionalization of the diester. The diamide obtained is subsequently reduced to result in the C-functionalized cyclam. Numerous cyclams C-substituted at the carbon atom in the 6 position have been synthesized by this route2-11. This approach has also made possible the production of biscyclams connected via carbon atoms12-14 and the synthesis of C-functionalized 1,4,7,10-tetraazatridecanes (2223)3,15,16. Finally, the anchoring of cyclic tetraamines to organic polymers has been carried out according to this reaction scheme17,18. The main advantage of this method is the possibility of introducing highly varied functional groups onto the macrocycle. However, it exhibits numerous disadvantages: it cannot be applied to the cyclen series, it requires a stage of reduction of the intermediate diamide carried out with a large excess of borane, and the reaction times are long, up to 20 days for the cyclization stage. Furthermore, the reaction yields remain low despite the optimization of the cyclization conditions19, 20.
Another method, represented by scheme 2, which consists of the Michael addition of a linear tetraamine to a coumarin or to an ethyl acrylate derivative and then a reduction with borane of the cyclic amide obtained, has made possible the production of cyclams C-functionalized in the 5 position by a phenol, nitrophenol21,22, pyridine23, imidazole24, hydroxypyridine25 or triphenylphosphine26 group. The disadvantages of this method are the same as those of the method of Tabushi et al.; the cyclization stage lasts three weeks at reflux in ethanol, the yield of the cyclization is low (8 to 40%) and it is subsequently necessary to reduce the intermediate amide.
The synthesis of 4-nitrobenzyl-cyclen (p-NO2-Bn-cyclen), a precursor of 2-(4-nitrobenzyl)-1,4,7,10-tetrakis (carboxymethyl)-cyclen (p-NH2-Bn-DOTA), has formed the subject of several publications and patent applications5,27-30. The synthesis represented by scheme 3 involves synthons N-substituted by groups of tosyl type and is directly inspired by the method of producing cyclen according to Richman and Atkins31.
Other C-functionalized cyclens have also been obtained by this method 32-36. While the cyclization yields are generally good, the disadvantages of the method of Richman and Atkins are reencountered here, the drastic detosylation conditions, the sulfonamide intermediates and the not very economic aspect in terms of atoms involved (non atom economic), to which is to be further added the difficulty of obtaining the C-functionalized synthons. This approach has also been used for the synthesis of cyclams functionalized in the 637,38 or 539 positions or of larger C-substituted tetraazacyclo-alkanes37,38,40.
Another access route to macrocycles consists in using an external support, generally a metal cation, to bring the synthons into a conformation favorable to the cyclization reaction. A “template effect” is then referred to. This approach, which makes possible an effective synthesis of the cyclam41,42, has also been proposed for the production of C-functionalized macrocycles. The most widely used synthesis, represented by scheme 4, involves intermediates of Schiff base type43. The cyclization is generally carried out with nitroethane or diethyl malonate. Copper(II) complexes based on cyclam (2323) but also on macrocycles of different sizes (2223), (2333) or (3333) C-substituted by ester functional groups or nitro groups were thus obtained43-46. Free ligands mono- or di-C -functionalized by acid or amine groups can also be obtained starting from these complexes47-50. Bismacrocycles were also synthesized in this way51. The subsequent functionalization of the cyclam carrying an amino group, for example, makes possible access to new C-substituted macrocycles52. The yields observed during the cyclization reactions vary from 15 to 75% according to the compounds targeted. The disadvantages of the method are the removal of the metal ion, which requires conditions which limit the choice of the functional group introduced, and the impossibility of it being adapted to the cyclen series. The use of Fe(III) as support has recently made it possible to obtain several C-arylated cyclens with yields of 40% to 70%53-54.
Finally, some authors describe the synthesis of C-functionalized cyclens according to conditions of high dilution28,55-58. These high-dilution techniques, which are widely used in the field of macrocyclic chemistry, generally result in good cyclization yields but the high dilution constitutes a major obstacle to the preparation of said macrocycles on a large scale.
The inventors have thus sought to develop a novel process for the preparation of C-functionalized tetraazacycloalkanes.